Antipsychotics May Boost Respiratory Failure Risk in COPD

In a population-based, case-crossover study, more COPD patients had filled a prescription for antipsychotics 2 weeks before having acute respiratory failure compared with a control period several months prior (11.7% versus 8.8%), Meng-Ting Wang, PhD, of National Defense Medical Center in Taipei, and colleagues reported online in JAMA Psychiatry.

That translated to a significantly higher risk of respiratory failure during the first 2 weeks of antipsychotic use, independent of cardiogenic, traumatic, and septic factors (adjusted OR 1.66, 95% CI 1.34 to 2.05, P<0.001).

“The results of this study indicated a life-threatening adverse respiratory effect of antipsychotic treatment, which has been described previously only in case reports,” they wrote.

Antipsychotics have been linked to acute respiratory failure in case reports, but population-level data are lacking, the researchers explained. Also, this effect is of particular concern among COPD patients, who are already prone to respiratory failure and are commonly treated with antipsychotics.

For their study, the team looked at data from the Taiwan National Health Insurance Research Database for patients with COPD who were newly diagnosed with acute respiratory failure in the hospital or in emergency care settings from Jan. 1, 2000 to Dec. 31, 2011. The protocol excluded patients with prior acute respiratory failure, lung cancer, and cardiogenic, traumatic, or septic respiratory failure.

For the main outcome, the study compared self-reported use of antipsychotics in the two weeks before their respiratory failure with a control period of 75 to 88 days prior to the event.

Over a mean of 3.5 years, a total of 5,032 of the 61,620 COPD patients were diagnosed with acute respiratory failure.

The team found that more patients filled at least one prescription for an antipsychotic medication during the case period than during the control period (11.7% versus 8.8%), which corresponded to a significantly higher risk of acute respiratory failure (adjusted OR 1.66, 95% CI 1.34 to 2.05, P<0.001).

There was also a dose-dependent risk of acute respiratory failure associated with antipsychotics (aOR 1.35, 95% CI 1.19 to 1.52, P<0.001), which rose from a 1.52-fold risk for a low daily dose (95% CI 1.20 to 1.92, P<0.001) to a 3.74-fold risk for a high dose (95% CI 1.68 to 8.36, P=0.001).

“Reducing the dose of antipsychotics seems to be a plausible strategy for lowering the risk of acute respiratory failure, but does not completely eradicate it, while high doses of antipsychotics should always be avoided whenever possible,” Wang and colleagues wrote.

The increased risk persisted under a case-time-control analysis (aOR 1.62, 95% CI 1.16 to 2.27, P=0.005) and nested case-control study (aOR 2.16, 95% CI 1.91 to 2.15, P<0.001). Also, both typical and atypical antipsychotics were found to have similar risks.

The exact mechanisms by which antipsychotics may be tied to a greater risk of respiratory failure, particularly in COPD patients, remain unclear, but the researchers proposed several plausible pathways. For example, it could be that serotonin, dopamine, and histamine agonists activate the respiratory pattern generator in the brainstem — an effect that could be inhibited by antipsychotics. Or, blocking dopamine D2 receptors could induce dystonia in the larynx, causing difficulty breathing. Finally, a loss of serotonin 5HT2Aactivity in the medulla could lead to the collapse of upper airway muscles.

The study was limited by the potential for confounding by indication, since psychosis can worsen patients’ lung function. Another limitation was that the ICD codes for acute respiratory failure were not ascertained, and important confounders like lung function test results and smoking status were not available.

Still, Wang and colleagues concluded that doctors should be cautious when prescribing antipsychotics to patients with COPD, and should avoid high doses if possible.